Fenretinide: History, Properties & Uses
The Active Ingredient in SciTech’s Lead Drug Candidate
History of Fenretinide
The active pharmaceutical ingredient (API) fenretinide (4-hydroxyphenylretinamide or 4-HPR) was first synthesized in the late 1960's by Robert J. Gander at the Johnson & Johnson (J&J) pharmaceutical company. At that time retinoic acid, parent compound of fenretinide, was known to be a useful drug in dermatological applications, particularly for the treatment of acne.
After its synthesis and characterization, the dermatological activity of fenretinide was assayed by J&J and it was found not to be active in any of their intended dermatology applications, so they abandoned fenretinide as a potential drug product. Historically, foremost in the thoughts of big pharma (including J&J) in the 1970's was the potentially large and lucrative dermatology market.
There was essentially no interest in the use of retinoids (the class of chemicals that include fenretinide) for the treatment of cancer. The use of retinoids in cancer changed dramatically when Ted Breitman at the NIH (National Institutes of Health) showed that retinoic acid could induce normal differentiation of leukemia cells (converted cancer cells into a normal neutrophils). This finding lead to retinoic acid, specifically all-trans retinoic acid (ATRA or tretinoin), being a cure for acute promyelocytic leukemia (APL), a previously fatal disease.
J&J later transferred the fenretinide drug, for purposes other than dermatology, to the National Cancer Institute (NCI) where NCI scientists did some of the very first animal studies to show that synthetic retinoids could prevent cancer in many organs, including breast, lung, bladder, prostate, and others. Fenretinide was shown to be particularly effective for the prevention of prostate cancer in rats, which has never been tested clinically.
Fenretinide was first deployed as an agent to prevent breast cancer in experimental animals in the 1970’s. It was then successfully used in human studies to prevent pre-menopausal breast cancer in thousands of high-risk Italian women in a 5-year clinical trial. In this human trial, it was also observed that there was a benefit for prevention of ovarian cancer; however, these results were never pursued or studied further in any significant way.
Fenretinide, being synthetic, was patented by J&J in the 1970s and is currently in the public domain (off-patent). In the late 1990s, J&J assigned their Investigational New Drug application (IND) as well as their entire fenretinide drug substance inventory to the National Cancer Institute (NCI). The NCI has since sponsored the development of several fenretinide cancer drug investigations.
In the original drug formulation for the treatment of cancer, the poorly-soluble fenretinide drug was dissolved (solubilized) in vegetable oil in extremely large gelatin capsules. These capsules are not a practical way to deliver a suitably high, therapeutic dose of fenretinide to a cancer patient even though they sufficed for the smaller dose needed for the Italian breast cancer prevention study.
Over the years, there have been dozens of intensive basic science studies of fenretinide. Many new aspects of its mechanism of action (MOA) have been uncovered and described; most notably, its unique and significant induction of apoptosis (programmed cell death). This apoptosis MOA is not observed in cancer cells with other retinoids of the same drug class as fenretinide. This observation has generated many new attempts to find a more practical, bioavailable dose of fenretinide for the treatment of cancer.
One such drug preparation for overcoming the limited bioavailability of fenretinde has been developed; notably, a fenretinide emulsion drug formulation for intravenous administration. However, this preparation is reported to contain significant amounts of egg phospholipids and soybean oil which reportedly causes dose limiting toxicities due to hypertriglyceridemia. Moreover, the concentration (or potency) of fenretinide in this drug formulation is relatively low and drug infusion must be administered over a relatively long, prolonged period of time (1 day at an in-patient clinic). In spite of these limitations, useful clinical responses in cancer patients have been reported and published using this fenretinide emulsion formulation.
The problem of how to deliver a safe and effective dose of fenretinide in order to achieve adequate, therapeutic blood levels of the drug in a cancer patient had remained unsolved for more than 40 years.
SciTech directly addresses these identified shortcomings of fenretinide bioavailability as well as the problems associated with the fenretinide emulsion formulation (hypertriglyceridemia and long infusion times). As such, SciTech’s ST-001 nanoFenretinide lead drug candidate is particularly important and welcomed.
SciTech’s new nanoFenretinide formulation promises to be a great improvement over the fenretinide emulsion formulation. SciTech's new drug candidate promises to achieve a safer, more effective and therapeutic dose of fenretinide. The new SciTech drug candidate is a patented fenretinide nanoparticle suspension which is free of triglycerides and can be intravenously administered to patients over a relatively short period of time (4 hours in an out-patient clinic). SciTech's lead ST-001 nanoFenretinide drug candidate is practical, economical and ready to be used in the clinic for the treatment of T-cell lymphoma with small cell lung cancer (SCLC) soon to follow. Various regulatory approvals by the FDA, to make widespread clinical use happen as soon as possible, are being vigorously pursued by SciTech.
Fenretinide is a synthetic analog of the naturally occurring retinol (vitamin A) and retinoic acid compounds. Molecularly, the three compounds differ only in their terminal functionality (far right of molecule structures, as shown below) ending in either an alcohol functionality (hydroxyl group), acid functionality (carboxyl group) or amide functionality (4-hydroxyphenyl group) for retinol, retinoic acid and fenretinide, respectively. These minor structural differences translate into significant differences in their respective biological properties.
Retinol (Vitamin A) Retinoic Acid Fenretinide
Fenretinide is a relatively small molecule that has been extensively studied and well characterized. Summarized in the table below (table scrolls) are some of its more common chemical, physical and structural properties. Fenretinide, being a hydrophobic molecule, is not water soluble and as such has had limited bioavailability as a drug, historically.
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Over the years, the NCI and other researchers have generated a large body of data and information that is available for public use and review. This body of data can be readily accessed via the database identifiers provided in the table below (table scrolls).
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Use of Fenretinide in Humans
Contributed by Ralph Parchment, Ph.D.
The history of fenretinide use in humans is a fitful series of discoveries about its unique therapeutic properties followed by clinical trials to evaluate these properties - using suboptimal pharmaceutical compositions that happened to be readily available at the time. In hindsight, it is not surprising that these suboptimal formulations failed to realize the full potential of fenretinide as an anticancer drug.
The substantial body of medical literature shows that fenretinide has significant anticancer activity in experimental and clinical settings. The drug destroys cancer cells by selectively inducing apoptosis. Clinically, the drug is effective at treating and preventing cancer when blood plasma levels of fenretinide reach the minimum therapeutic threshold for several days. Because of the poor systemic bioavailability of fenretinide, it has not been possible to achieve that minimum therapeutic threshold safely and so it has not been possible to achieve the drug’s full therapeutic potential, until now.
Particularly noteworthy human studies include the following: (1) Large breast cancer chemoprevention study (approx. 3000 patients, 5 year study) demonstrating fenretinide to be well-tolerated in humans; (2) NCI case report confirming tumor response in an advanced cutaneous T-cell lymphoma (CTCL) patient - an early efficacy signal; (3) ASCO (American Society of Clinical Oncology) paper confirming therapeutic responses in the treatment of CTCL and angioimmunoblastic T cell lymphoma (AITL) that also highlights the shortcomings of the fenretinide emulsion product, and (4) Phase II clinical study showing fenretinide to be well-tolerated in patients with small-cell lung cancer (SCLC) as well as a stabilization of the disease in 30% of the patients.
As a safer analog of vitamin A, fenretinide entered the clinic as a relatively low strength formulation dissolved in corn oil which was loaded into a soft gel cap (100 mg) designed for oral administration in chemoprevention studies. The resulting clinical studies reported efficacy, especially in premenopausal women, but fenretinide failed to displace tamoxifen in this setting and interest waned.
Fenretinide acquired a reputation as a chemotherapeutic agent based on reports of its ability to induce apoptosis, distinguishing it mechanistically from the naturally occurring retinoids. The Cancer Therapy Evaluation Program (CTEP) at the NCI sponsored dose-escalation Phase 1 trials of fenretinide to establish its maximum tolerated dose (MTD) and safety profile. However, without re-formulation to deliver the higher doses, it was perhaps not surprising that chemotherapeutic plasma levels could not be achieved due to limits on oral bioavailability.
The NCI CTEP studies recommended a Phase 2 Dose (RP2D) of fenretinide at 900 mg/m2 bid (b.i.d. or BID, twice a day; from the Latin "bis in die", meaning twice a day), which was not defined by toxicity (as is usual) but rather by the dose associated with achieving maximum possible Cmax (the maximum or peak serum concentration of the drug) and AUC (Area Under the Curve; a plot of drug concentration in blood plasma vs. time) in >80% of patients. Unfortunately, the achievable Cmax was 2-3 fold below concentrations needed for apoptosis as reported in preclinical models; and, the Phase 2 results were predictable: modest disease stabilization but no regression in SCLC and no significant activity in renal cell cancer associated with sub-therapeutic intratumoral drug levels in biopsies.
A Phase II study in ovarian cancer reported an association between efficacy and a steady state plasma concentration >9 µM (micro molar), but concluded that formulations with improved bioavailability were still needed. An investigational oral formulation of fenretinide complexed with Lym-X-Sorb® (LXS), a commercial lipid product from BioMolecular Products Inc., only modestly improved oral bioavailability in pediatric patients (average Cmax of 21 µM) with predictable modest efficacy. Similar results were obtained from a Phase 1 trial of the fenretinide:LXS complex in adult patients leading the authors to state in the paper’s abstract “Better fenretinide formulations are needed to… achieve the consistent systemic exposures associated with activity in preclinical models”. However, this Phase 1 report did note that 1 of 2 CTCL patients experienced disease stabilization with improvement in pruritus and resolution of skin infections despite poor drug bioavailability.
The experience to date suggests an inherent limitation of oral bioavailability of fenretinide so it seemed prudent to pursue injectable formulations that would circumvent the problem altogether. The first intravenous (IV) formulation was developed and patented under the National Cancer Institute's (NCI's) Rapid Access to Intervention Development (RAID) program: an IV fenretinide emulsion formulation containing 2 mg/mL fenretinide. In the NCI-RAID sponsored Phase 1 clinical trial, clinical responses were reported in three patients, not including a transient response in non-Hodgkin lymphoma (NHL) at a low dose level (reported at ASH 2007). It is striking to note that these three cases were T-cell NHL: one case of cutaneous T-cell lymphoma (CTCL) and two cases of angioimmunoblastic T-cell lymphoma (AITL).
Human Responses in the Phase 1 Clinical Trial of Fenretinide Emulsion (qdx5 CIVI q3wk)
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The case report of the durable CTCL response described a 28 year old female presenting at the NCI clinic with stage IV Sézary Syndrome (SS) after 3 cycles of the CHOP regimen (Cyclophosphamide; Hydroxydaunorubicin aka doxorubicin or adriamycin; Oncovin aka vincristine; and, Prednisone) and one cycle of gemcitabine, during which Sézary cells appeared. At the NCI, she received three protocols over nine months with a mixed response: standard bexarotene, a phase II histone deacetylase inhibitor (romidepsin) and a phase II immunotoxin. In stark contrast, six cycles of fenretinide-emulsion achieved a confirmed tumor response, and 26 cycles achieved sustained CR and no evidence of pruritic plaques or erythema. Significantly, this CTCL patient had prior unsuccessful bexarotene and HDAC (histone deacetylase ) therapies indicating a lack of cross-resistance of fenretinide.
The CTCL case is an early efficacy signal of fenretinide in mycosis fungoides/ Sézary syndrome (MF/SS), analogous to the serendipitous efficacy signals in MF/SS patients from Phase 1 trials of bexarotene, vorinostat and romidepsin described above that eventually led to their approval as CTCL therapies; and, this early efficacy signal is the rationale for proposing CTCL as the disease target of ST-001 nanoFenretinide.
The efficacy signal of romidepsin in CTCL that arose from a NCI Phase 1 trial was pursued with a definitive Phase 2 trial; so, an important question is why the early efficacy signal of the fenretinide emulsion formulation was not similarly pursued into Phase 2. The reason appears to be the severe hypertriglyceridemia (Grade 4) associated with the efficacious dose levels and the fact that 2 of 3 clinical responses, including the SS patient who did not experience this toxicity, occurred at dose levels at or above the Recommended Phase 2 Dose (RP2D) of 905 mg/m2/day (see row 1 in the table above).
These findings point to a strategy to finally realize the clinical potential of fenretinide: intravenous administration of the drug coupled with the highest possible strength formulation to minimize any contribution of the load of lipid excipients to hypertriglyceridemia (the fenretinide emulsion potency was 2 mg/mL). SciTech dropped its pursuit of the use of emulsions when it became clear that it was limited to strengths of about <6 mg/mL (unpublished data), and instead launched an R&D program to design a lipid carrier-based approach specifically to support high strength fenretinide formulations.
A review of the use of fenretinide as an experimental therapy in pediatric or childhood cancer can be found elsewhere (www.SciTechDevelopment.com/fenretinide-pediatric-cancer).
A brief overview of fenretinide as an experimental treatment in cancer combination therapy can be found at www.SciTechDevelopment.com/fenretinide-drug-combinations.
Fenretinide Drug Mechanism of Action (MOA)
There is ample evidence in the scientific literature that demonstrates that fenretinide is selectively cytotoxic and destroys cancer cells by inducing apoptosis (a form of programmed cell death). It has been shown that fenretinide generates several apoptosis-mediating agents such as ceramides, reactive oxygen species (ROS), and ganglioside.
In simple terms:
The fenretinide drug recognizes a structure on the surface of cancer cells and binds (or attaches) to it.
This “surface structure” is comprised of protein(s) known as retinoic acid receptors (RARs).
Binding of the drug to the receptor initiates the sending of chemical signals inside the cell that eventually leads to cell death.
This cell death mechanism is called apoptosis (from the ancient Greek word ἀπόπτωσις or "falling off").
The drug also works by other, as of yet, unknown mechanism(s) since fenretinide kills cancer cells that do not have the retinoic acid receptors (RARs).
More sophisticated illustration of the above summary (see diagram below):
Fenretinide (yellow box FEN) enters the cancer cell.
The arrows represent a cascade of chemical signals that occur inside the cell (known as signaling pathways).
Activation of this cascade of signals or chemical pathways (represented by arrows) is triggered by the binding of fenretinide to its receptors.
The eventual outcome of this cascade of activity is cell death (apoptosis).
Recently, fenretinide has been shown to reactivate the immune system in the treatment of lymphoma. The fact that fenretinide induces multiple apoptosis mediators, and a likely immune response, has served as the basis of predictions regarding its efficacy in so many different types of cancer.
The most common side effects reported with oral, lower dose fenretinide use include skin dryness and night-blindness, which are both reversible upon cessation of the fenretinide treatment; and, with intravenous higher doses of the fenretinide emulsion, additional side effects include elevated triglyceride blood levels.
SciTech’s History with Fenretinide
SciTech Development LLC was formed as a spin-off from the Karmanos Cancer Institute (KCI) and Wayne State University (WSU). As a recipient of a U.S. Small Business Innovation Research (SBIR) grant, SciTech’s research focused on oncology drugs, specifically on fenretinide.
Fenretinide had shown great promise as a cancer drug. However, fenretinide does not easily dissolve in the body, so it cannot get to cancer cells in high enough doses, which severely limited its effectiveness. The National Cancer Institute (NCI) issued a challenge to find a way to deliver fenretinide to cancer cells in greater concentrations, but without adverse or toxic side effects.
SciTech subsequently received an SBIR grant from the NCI and successfully delivered on the promise of fenretinide. We developed and patented our first drug candidate ST-001 nanoFenretinide and proprietary SciTech Drug Delivery Platform (SDP).
Louis M. Scarmoutzos, Ph.D.